Following glucose entry, it is first phosphorylated and then is converted to fructose 6-phosphate and glyceraldehyde 3-phosphate (G3-P) (Jandeleit-Dahm& Cooper, 2006). By the action of various transferases and phosphatases, G3-P forms glycerol phosphate, a precursor of diacylglycerol (DAG) and a well-known signaling molecule (Brognard& Newton, 2008). The fructose 6- phosphate is also converted to glucosamine-6-phosphate by glutamine: fructose-6-phosphate-aminotransferase. The latter modulates promoter activities of ECM modulating TGF-b1 and PAI-1 by phosphorylating transcription factor Sp1(Mason &Wahab, 2003). Under the condition of high glucose ambience, there is an elevated role of accessory polyol pathway; as a result of which, the glucose is reduced to sorbitol by a NADPH-dependent enzyme, aldose reductase (AR) (Chung et al, 2003). The sorbitol is oxidized further to fructose by sorbitol dehydrogenase utilizing NADþ as a co-factor, leading to relative depletion of NADPH and reduced glutathione (GSH), an increase in the NADH/NADþ ratio, and decreased levels of nitric oxide (NO), paving way to altered cellular redox and oxidant and osmotic stress. The relevance of polyol pathway in diabetic lesions is vague; however, lowered levels of GSH in the eye lens in mice overexpressing AR have been reported (Chung et al., 2003). Another enzyme pertinent to glucose metabolism is myo-inositol oxygenase (MIOX) (Nayak et al., 2005). It is expressed in the tubular epithelium and is responsible for the oxidation of myo-inositol generated from glucose 6-phosphate after a series of steps. Phosphatidylinositol, a metabolic product of myo-inositol is involved in cellular signaling and osmoregulatory functions of the kidney. MIOX expression is up-regulated in experimental diabetes, while the renal concentration of myo-inositol decrease and its supplementation normalizes glucose-induced proliferation and collagen synthesis in tubular cells (Haneda et al., 2003), thus linking its role in diabetic nephropathy.
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3.3. Relevance of AGEs in the Pathogenesis of Diabetic Nephropathy:
AGEs are the heterogeneous groups of macromolecules that are normally non-enzymatically produced by the consequent interaction of reducing sugars with free amino groups of proteins, lipids, and nucleic acids, but their formation is elevated under circumstances of high glucose levels. Initially a labile Schiff base is formed that undergoes a series of chain reactions, i.e., Amadori rearrangement, dehydration, polymerization, and ultimately drives toward formation of AGEs’. The AGEs are formed both extracellularly from glucose and intracellularly from various dicarbonyls. The extracellular AGEs interact with their receptor, RAGE, and other binding proteins, that is, OST-48, 80K-H, galectin-3, and induce various intracellular events (Tan, 2007). The intracellular AGEs also cause initiationof several signaling events by activating PKC, MAP kinase, and transcription factors such as NF-jB, thus increasing the activity of various growth factors, such as TGF-b, thereby altering the expression of ECM proteins (Jakuš&Rietbrock, 2004). The latter include raised synthesis of type I and IV collagens, lowered expression of proteoglycans, and anomalous ECM polymerization and expansion. Intriguingly, the AGEs themselves can covalently bind with proteins, thus compounding their harmfulaftermaths in various tissues (Jakuš&Rietbrock, 2004). In addition, there are perturbed cell-matrix interactions, altered adhesiveness, and capillary permeability. These ECM vascular anomalies partially reverse by a resultant interruption in AGE:RAGEinteractions (Thallas-Bonke et al., 2004). Another important AGEs induced cellular event includes the formation of reactive oxygen species (ROS) that as well brings about modulation of the activity of various kinases and transcription factors that ultimately contribute to ECM pathology (Tan 2007, Li &Gobe, 2006).
Although there are present various signalling kinases, PKC appears to be a centerpiece in the pathogenesis of diabetic nephropathy (Li &Gobe, 2006). Under the condition of high glucose level it is activated by DAG formed during glycolytic intermediary steps and by ROS generated following AGE: RAGE interactions (Tan 2007;Inoguchi et al., 2003). Suchinteractions at the cell membrane cause activation of PKC by elevating the activity of phospholipase C with an increase in intracellular Ca2þ and DAG. This cyclic generation of DAG suggest an intimate ‘‘level and activity’’ relationship between DAG and PKC, and such a parallelism in their expression in various tissues in diabetes (Inoguchi et al., 2003). Furthermore, the PKC activation leads to endothelial dysfunction with lowered nitric oxide production, raised endothelin-1 expression, and vascular endothelial growth factor; followed by an alteration in blood flow and capillary permeability that are compounded by increased TGF-b1–induced synthesis of integral ECM proteins of the vasculature (Inoguchi et al., 2003). At the same time, increased expression of NF-jB and PAI-1 results in induction of a local tissue inflammatoryresponse and thrombotic microangiopathy, thus accentuating the vascular injury, which is further augmented by additional ROS generated by plasmalemmal NADPH oxidoreductase (Tan, 2007). The fact that PKC activation occurs by means of multiple routes and that the administration of PKC inhibitor, ruboxistaurinmesylate causes reduction in renal abnormalities in db/db mice suggests its central signaling function in hyperglycemia induced vascuvascular injury (Tan 2007;Inoguchi et al., 2003).
The AGEs, ROS, DAG, PKC, and hexosamines are among the effective candidates that causes activation of TGF-b signalling(Leask et al., 2004), whereasmany others compounding the hyperglycemic injury include vasoactive substances, that is, angiotensin II, endothelin, and thromboxane, and cyclical stretch and relaxation of mesangial cells mimicking intraglomerularhypertension(Wolf, 2006). The final result is anabnormalbuildup of ECM proteins, which is further facilitated by an inhibition of matrix proteases (MMPs) and subsequent activation of the corresponding inhibitors (TIMPs). Presently, TGF-b is considered as the major cytokine responsible for ECM pathobiology depicted in diabetic nephropathy(Ziyadeh, 2004). Initially, TGF-b binds to a type II receptor, which Trans-phosphorylates type I-serine/threonine kinase receptor. The latter then initiates interaction with Smad2 and 3, forming a complex with Co-Smad4(Schiffer et al., 2000). Following the nuclear translocation of this complex, it binds with promoters of TGF-b target genes, e.g., collagen a 1(I), PAI-1, Jun B, c-Jun, and fibronectin and regulates their transcription. Altogether these events are under negative regulation by Smad7. Besides Smads, the mitogen activated protein kinases (MAPKs) involved in hyperglycemia-induced TGF-b signalling comprise extracellular signal regulated kinases 1 and 2 (ERK1 and 2, p44/p42 MAPKs), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/ SAPK), and p38 MAP kinase(Schiffer et al., 2000). The MAPKs also causes modulation of transcriptional regulation of ECM genes via activated protein-1 (AP-1), a heterodimer of c-Fos and c-Jun. As AP-1, being regulated by ERK and JNK, can bind to Smad3 while Smad3 and Smad4 complex to AP-1 consensus sequences in different promoters of TGF-b target genes, suggesting a cross-talk between Smad and MAPK pathways activated by high glucose ambience (Schiffer et al., 2000). Another cytokine relevant to TGF-b signalling is connective tissue growth factor (CTGF) that is induced by TGF-b via consensus Smad and transcription enhancer factor (TEF) elements localized within the CTGF promoterregion (Ito et al., 2010). The above mentioned signalling has been worked out in mesangial cell culture systems, and itsin vivo relevance is also well defined in mice models of diabetes, where raised TGF-b bioactivity has been observed. Moreover, administration of neutralizing anti–TGF-b antibodies results in prevention of renal hypertrophy, mesangial matrix expansion, increased collagen and fibronectin mRNA expression, and deterioration of renal functions in db/db or STZ-induced diabetes in mice(Ziyadeh, 2004). Similarly it’s up-regulated tissue expression and elevated urinary excretion of TGF-b in patients with diabetic nephropathy has been observed. Angiotensin-converting enzyme inhibitors that improve renal damage concurrently also results in lower TGF-b production, thus suggesting a relationship of hypertension and ECM pathophysiology in diabetes mellitus(Wolf, 2006).
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The ROS related to the common denominators and amplifiers of signalling cellular pathways are thus activated by hyperglycemic condition(Brownlee 2000;Tan 2007;HA & LEE, 2005). They are continuously being produced and degraded in normal condition formaintenance of homeostasis, but when there development and production reaches high concentrations, such as during hyperglycemic milieu, they then turn capable enough to induce injury in different organs of the body(Lee et al., 2003). The ROS that can cause renal injury include;the superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical, and peroxynitrite(DjordjeviÄ‡, 2004). They have their redox balance maintained by different enzymes, such as, cytoplasmic Cu/Zn superoxide dismutase (Cu/ZnSOD) and mitochondrial manganese SOD (MnSOD), the most important is heme oxygenase-1(HO-1) that undergo notable induction by hyperglycemia(Koya et al., 2003). Many of the ROS are produced during the period of mitochondrial oxidative phosphorylation and small amounts via NADPH-oxidase system(Nony&Schnellmann, 2003; Abuelo, 2007; Basile, 2007). During the time of oxidative phosphorylation the electron donors bring about production of high membrane potential by pumping protons across the mitochondrial inner membrane(Brownlee, 2000; Starkov et al., 2004). As a result, the electron transport is held inhibited and the half-life of free-radical intermediates of ubiquinone subsequently elevates, resulting in reduction of O2 to O2- with ensuing oxidant stress. Rotenone, which is an inhibitor of electron transport, causes blockage of the DCF sensitive ROS generation, and the fact that a similar effect is exhibited by over expression of mitochondrial MnSOD or uncoupling protein-1 (UCP-1) supports this notion(Brownlee, 2000;Heyman et al., 2010).The MnSOD or UCP-1 reverses the oxidant stress produced by the high glucose-induced cellular events, including the polyol and hexosamine fluxes, AGE formation, and PKC activation. Though, O2 – generated initially (vide supra) causes inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) that in turn results in amplification of thesecellular events with repetitive ROSproduction (Ha & Lee,2006). Similarly, the gene disruption of GADPH also causes amplification of the above cellular event; supporting the notion of function of mitochondrial ROS in hyperglycemia-induced injury and ECM buildup. The overexpression of extra-mitochondrial cytoplasmic Cu/ZnSODresults in reduction of the glomerular pathophysiologic alterations in db/db mice and STZ-induced diabetes(Friedewald& Rabb, 2004; Cerdá et al., 2008). The ROS are generated via the system involving NADPH-oxidase by the interaction of membrane-bound flavocytochrome b558 (heterodimer of gp91phox and p22phox) with various cytosolic proteins (p47phox, p67phos, p40phox, and a GTP-binding protein, p21rac) (Abuelo, 2007; Metcalfe et al., 2002), as a result of which O2 is generated, thereby getting dismutated to H2O2. The utter relevance of this system in renal pathobiology lies in the fact that Nox 4, a homologue of neutrophil gp91phox, is expressed in the kidney(Abuelo, 2007). Alongside AGEs, PKC, DAG, IP3 (inositol 1, 4, 5-trophosphate), and TGF-b, the metabolites of cyclo-oxygenase (COX) pathway can also result in activation of NADPH oxidase under the high glucose environment (Lee et al., 2003;Heyman, 2010). Moreover, decreased fibronectin expression by the inhibitors of oxidase, apocynin, and diphenyleneiodonium (DPI) presents the effective and influential role of NADPH oxidase in hyperglycemic injury and its relevance in redox-sensitive pathways, that is, cell growth, apoptosis, migration, and extracellular matrix (ECM) modeling that are modulated by different signaling pathways and transcription and growth factors such as TGF-b. The latter causes an adverse effecton the biology of tubular cells with induction of epithelial-mesenchymal transition, and loss of epithelial cell adhesion, a-smooth muscle actin expression, cytoskeletal organization, and cell migration through the basement membrane and ensuing of tubulo-interstitial fibrosis(JHA & CHUGH, 2003).Different systems in which ROS are generated include nitroso-redox balance, where reactive nitrogen species (RNS), e.g., derivatives of NO, are generated(Nash et al., 2002).A cofactor of nitric oxide synthase (NOS), which is known as tetrahydrobiopterin (BH4) beings about modulation of NO synthesis (Prakash et al., 2003).In high glucose condition, BH4 levels are reduced with a reduced synthesis of NO by the endothelium, further leading toward an altered ratio of BH4 and its oxidized form, BH2, with increased generation of superoxide(Wang et al., 2005). More support understanding the role of RNS in pathogenesis of hyperglycemic injury is derived from the various studies that elucidate an amelioration of endothelial and smooth muscle dysfunction in diabetic rat aortic rings exposed to BH4(Wang et al., 2005).
Similarly like the ROS that cause amplification of the hyperglycemic injury, hypertension, and mostly an elevated glomerular capillary pressure,ROS also effectively and potentially contribute to in accelerating diabetes related complications, by a cross-talk between metabolic and hemodynamic factors that are considerably operative under high glucose environment, which is a concept, arosein recent years. Various micropuncture studies in experimental diabetes demonstrated the occurrence of intraglomerular hypertension, with a normal evidence of systemic blood pressure. This referred to the observation that hyperglycemia impairs autoregulation of local glomerular microcirculation with dilatation of arterioles, more so of the afferent arteriole, affecting the transcapillary hydraulic pressure difference and plasma flow. Hyperglycemia causes sensitization of the target organs to blood pressure induced damage, mostly by renin-angiotensin system (RAS) activation with local angiotensin II (Ang II) production in the kidney. The support for this idea comes from various studies in which lowered blood pressure had comparable or even more beneficial effects, e.g., on microalbuminuria, than controlling hyperglycemia. The cells that may be involved in the activation of local RAS include
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